This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Atherosclerosis is chronic inflammation of the arterial wall. It is characterized by accumulation of oxidized low-density lipoprotein and by recruitment of monocytes that differentiate into foamy macrophages. Chemokines produced at sites of vascular inflammation stimulate leukocyte entry into plaques. Although chemokines are considered promoters of atherogenesis, the chemokine CXCL16, which is expressed on foamy macrophages of human and murine atheromas, protects against atherosclerosis by unknown mechanisms. Our data indicate that CXCL16 stimulates cholesterol efflux from human foamy macrophages to the hypolipidated acceptors high-density lipoprotein and apolipoprotein AI, two major atheroprotective molecules that transport atherogenic cholesterol to the liver for metabolism and excretion through the biliary tract. Cholesterol removal from the body is known as reverse cholesterol transport, a fundamental mechanism protecting against atherosclerosis. Using mouse models, we will investigate the role of CXCL16 in reverse cholesterol transport and test whether CXCL16 protects against atherosclerosis in a hematopoietic cell-specific manner. Human macrophage CXCL16 is a scavenger receptor for oxidized lowdensity lipoprotein that regulates expression of the atheroprotective cellular cholesterol transporters (ABCA1 and ABCG1) and apolipoprotein E. Therefore, we will also investigate whether CXCL16 as a scavenger receptor regulates expression of atheroprotective genes in vivo.